Novel diphosphines, their complexes with transisition metals and their use in asymmetric synthesis

ABSTRACT

The invention relates to novel diphosphines, in optically pure or racemic form, of formula (I):  
                 
 
     in which:  
     R 1  and R 2  are a (C 5 -C 7 )cycloalkyl group, an optionally substituted phenyl group or a 5-membered heteroaryl group; and  
     A is (CH 2 —CH 2 ) or CF 2 .  
     The invention further relates to the use of a compound of formula (I) as a ligand for the preparation of a metal complex useful as a chiral catalyst in asymmetric catalysis, and to the chiral metal catalysts comprising at least one ligand of formula (I).

[0001] The present invention relates to novel racemic or chiraldiphosphines useful as bidentate ligands in the synthesis of metalcomplexes and, more particularly, catalysts intended especially forcatalytic asymmetric hydrogenation.

[0002] Asymmetric catalysis has the advantage of affording the directpreparation of optically pure isomers by asymmetric induction withoutthe need to resolve racemic mixtures. The prior art has alreadydescribed certain diphosphorus ligands commonly used in the preparationof metal complexes for the asymmetric catalysis of hydrogenationreactions, carbonylation reactions, hydrosilylation reactions, reactionsfor the formation of C—C bonds or even reactions for the asymmetricisomerization of allylamines.2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) or[(5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl]bis-(diphenylphosphine)(SEGPHOS), described in the patent application published under thenumber EP 850 945, may be mentioned in particular.

[0003] It is desirable to develop novel chiral ligands in order toimprove the selectivity of reactions (diastereoselectivity andenantioselectivity).

[0004] The present invention therefore relates to novel diphosphinederivatives, in racemic or optically pure form, of formula (I):

[0005] in which:

[0006] R₁ and R₂ each independently are:

[0007] a (C₅-C₇)cycloalkyl group, a phenyl group optionally substitutedby one or more (C₁-C₄)alkyl, (C₁-C₄)alkoxy or di(C₁-C₄)alkylamino groupsor by a halogen atom, or

[0008] a 5-membered heteroaryl group; and

[0009] A is an ethylene group (CH₂—CH₂) or a CF₂ group.

[0010] 5-Membered heteroaryl group is understood as meaning e.g. a2-furanyl, 3-furanyl, 2-benzofuranyl or 3-benzofuranyl group.

[0011] Alkyl is understood as meaning a linear or branched, saturatedhydrocarbon group.

[0012] (C₁-C₄)alkyl is understood as meaning an alkyl group containingfrom 1 to 4 carbon atoms.

[0013] The term ‘alkoxy’ denotes an O-alkyl radical in which alkyl is asdefined above.

[0014] Halogen atom is understood as meaning a chlorine, bromine,fluorine or iodine atom.

[0015] According to one particular feature, the present inventionrelates to the compounds of formula (I) in which R₁ and R₂ are identicaland, more particularly, in which R₁ and R₂ are identical and are aphenyl group.

[0016] The compounds of formula (I) according to the present inventioncan be prepared by the process shown in SCHEME 1 below, in which R₁, R₂and A are as defined for (I) and R is a (C₁-C₄)alkyl group or anoptionally substituted phenyl group.

[0017] The compound of formula (I), in optically pure form, (R) or (S),or in racemic form, can be prepared by reducing the compound of formula(IIA):

[0018] in which R₁, R₂ and A are as defined for (I), respectively in thecorresponding optically pure form, (R) or (S), or in the racemic form,for example by reaction with a reducing agent, such as trichlorosilane,in the presence of an amine, such as tributylamine.

[0019] The compound (IIA) in optically pure form is obtained e.g. byresolving the compound (IIA) in racemic form via the formation of acomplex with (−)-L-dibenzoyltartaric acid or (+)-D-dibenzoyltartaricacid or with other chiral acids, as described in the prior art for thistype of resolution.

[0020] The enantiomers can also be prepared by separation via chiralphase chromatography.

[0021] The compounds of formula (IIA), in racemic or optically pureform, which are intermediates in the synthesis of the compounds offormula (I), are novel compounds and form an integral part of theinvention.

[0022] The compounds of formula (IIA) can be prepared from the compounds(MA):

[0023] in which R₁, R₂ and A are as defined for (I), by reaction with anorganolithium compound, such as tert-butyllithium, in the presence ofiron trichloride or another appropriate oxidizing agent.

[0024] The compounds (IIA) can also be prepared from the derivative(IIIA) in two steps: iodination of the compound (IIIA) to give an iodinederivative of formula (IIIC), followed by an Ullman-type couplingreaction with the aid of copper.

[0025] The compounds (IIA) in which R₁ and R₂ are identical can beprepared in a third way from the compounds of formula (IIB) in which Ris a (C₁-C₄)alkyl group or a substituted or unsubstituted phenyl group.In this third process the compounds (IIB) are brought into contact withan organometallic compound of the formula R₁Li or R₁MgX, in which R₁ isas defined for (I) and X is a halogen atom.

[0026] The compounds (IIB) can exist in racemic or chiral form and canbe resolved, like the compounds of formula (IIA), via chiral acids orchiral phase chromatography.

[0027] The compounds of formula (IIB) are novel and form an integralpart of the invention.

[0028] The compounds (IIA) in which R₁ and R₂ are identical can also beprepared from the compounds of formula IIB by a 2-step process of whichthe first step consists in reacting said compound IIB with thionylchloride, in the presence of a solvent, to give the halogen derivative(IIC):

[0029] and the second step consists in reacting said compound IIC withan organometallic compound, especially an organolithium compound of theformula R₁Li or an organomagnesium compound of the formula R₁MgX, inwhich R₁ is as defined for (I) and X is a halogen atom, to give theexpected compound of formula IIA.

[0030] The compound of formula (IIIA) can be prepared by oxidizing thephosphine of formula (IVA):

[0031] in which R₁, R₂ and A are as defined for (I), by reaction with asolution of hydrogen peroxide in methanol or with the aid of otherphosphine-oxidizing reagents well known to those skilled in the art.

[0032] The phosphine (IVA) itself can be prepared from the correspondingbromine compound (V) by reaction with an organolithium compound, such asn-butyllithium, and then with the phosphine R₁R₂PCl, where R₁ and R₂ areas defined for (I), at a temperature close to −70° C.

[0033] The compound (IIIA) can also be prepared directly from thecompound (V) by reaction with magnesium in tetrahydrofuran to form aGrignard reagent, followed by reaction with the phosphinyl chlorideR₁R₂P(O)Cl, where R₁ and R₂ are as defined for (I).

[0034] The compound (IIIA) can also be prepared from the compound (V)via the compound (IVA) by reaction with magnesium in tetrahydrofuran toform a Grignard reagent, followed by reaction with the phosphineR₁R₂PCl, where R₁ and R₂ are as defined for (I), and then by anoxidation reaction with a solution of hydrogen peroxide in methanol orwith the aid of other phosphine-oxidizing reagents well known to thoseskilled in the art.

[0035] The compounds of formulae (IIIA), (IIIC) and (IVA) are novel andform an integral part of the invention.

[0036] The derivatives of formula (IIB) can be obtained in one step fromthe derivative (IIIB), in which R is as defined for the derivative(IIB), by reaction with an organolithium compound, such assec-butyllithium, in the presence of iron trichloride or anotherappropriate oxidizing agent.

[0037] The derivatives of formula (IIB) can also be obtained in twosteps from the derivatives of formula (IIIB) by iodination to give theiodine derivatives (IIID), followed by an Ullman-type reaction withcopper to give the derivatives (IIB).

[0038] The compounds of formula (IIIB) can be obtained from thecompounds of formula (V) by reaction with magnesium in an ether to forman organomagnesium compound, and reaction of the latter with aderivative Cl—P(O)(OR)₂, in which R is as defined in (IIB).

[0039] The compounds of formula (IIIB) can also be obtained from thecompounds of formula (V) by reaction with nickel chloride at atemperature in the order of 100 to 160° C., in the presence of aderivative P(OR)₃, in which R is as defined for (IIB).

[0040] The compounds (IIIB) in which A is CF₂ are novel and form anintegral part of the invention. The compounds (IIIB) in which A isethylene and R is a phenyl, methyl or (C₃-C₄)alkyl group are novel andform an integral part of the invention.

[0041] A further feature of the invention relates to the use of acompound of formula (I) as a ligand for the preparation of a metalcomplex useful as a chiral catalyst in asymmetric catalysis.

[0042] The present invention further relates to the chiral metalcatalysts comprising at least one ligand of formula (I) in racemic or,preferably, optically pure form. In the case where the ligand of formula(I) is in racemic form, the chirality of the metal complex is obtainedvia another chiral ligand, for example of the chiral diamine type.

[0043] The metal catalysts according to the present invention may beused for the asymmetric catalysis of hydrogenation reactions,hydroboronation reactions of unsaturated compounds, olefin isomerizationreactions, allylic alkylation reactions and, in general, reactions forthe formation of C—C bonds (such as 1,4-additions of boronic acids),reactions for the asymmetric cyclization of 4-pentenals (J. Org. Chem.2000, 65, 5806-16), ene-yne cyclization reactions (Angew. Chem., Int.Ed. 2001, 40(1), 249-53), allylic substitution reactions of enolates(Angew. Chem., Int. Ed. 2000, 39(19), 3494-7) and reactions for theformation of aromatic α-amino acids (Angew. Chem., Int. Ed. 2000,39(22), 4114-6).

[0044] In one preferred embodiment of the invention, the metal catalystsare used for the hydrogenation of C═O, C═C and C═N bonds. The catalystswhich can be used in this type of reaction are preferably rhodium,ruthenium, palladium, iridium, nickel or copper catalysts.

[0045] In one particular embodiment, the invention relates to the chiralmetal catalysts of formula (VI):

M_(m)L_(n)X_(p)S_(q)  (VI)

[0046] in which:

[0047] M is a metal selected from rhodium, ruthenium, iridium,palladium, nickel and copper;

[0048] L is a chiral compound (I); and

[0049] X, S, m, n, p and q are defined as follows:

[0050] if M=Rh, then X=Cl, Br or I; m=n=p=2; q=0;

[0051] if M=Ru, then: X=—OC(O)CH₃; m=n=1; p=2; q=0;

[0052] or X=Br; m=n=1; p=2; q=0;

[0053] or X=Cl; S═N(CH₂CH₃)₃; m=n=2; p=4; q=1;

[0054] or X=methylallyl; m=n=1; p=2; q=0;

[0055] or X=Cl; S=pyridine; m=n=1; p=q=2;

[0056] or X=Cl; S=chiral 1,2-diamine; m=n=1; p=q=2 or p=2, q=1;

[0057] if M=Ir, then X=Cl, Br or I; m=n=p=2; q=0;

[0058] if M=Pd, then: X=Cl; m=n=1; p=2; q=0;

[0059] or X=π-allyl; m=n=p=2; q=0;

[0060] if M=Ni, then X=Cl, Br or I; m=n=1; p=2; q=0.

[0061] Examples of chiral diamines which may be mentioned are (R,R)- and(S,S)-1,2-diphenylethylenediamine.

[0062] One particular feature of the invention relates to the metalcatalysts of formula (VII):

[M_(r)L_(s)Z_(t)W_(u)]Y_(v)  (VII)

[0063] in which:

[0064] M is a metal selected from rhodium, ruthenium, iridium, palladiumand copper;

[0065] L is a chiral compound (I); and

[0066] Z, W, r, s, t, u and v are defined as follows:

[0067] if M=Rh, then Z=1,5-cyclooctadiene or norbornadiene; Y=BF₄, ClO₄,PF₆, OTf or BPh₄; r=s=t=v=1; u=0;

[0068] if M=Ru, then: Z=Cl, Br or I; W=benzene or p-cymene; Y=Cl, Br orI; r=s=t=u=v=1;

[0069] or Y=BF₄, ClO₄, PF₆ or BPh₄; r=s=1; t=u=0; v=2;

[0070] or Z=Cl; Y═NH₂(C₂H₅)₂; r=s=2; t=5; u=0; v=1;

[0071] if M=Ir, then Z=1,5-cyclooctadiene or norbornadiene; Y=BF₄, ClO₄,PF₆ or BPh₄; r=s=v=1; t=1; u=0;

[0072] if M=Pd, then Y=BF₄, ClO₄, PF₆ or BPh₄; r=s=v=1; t=u=0;

[0073] if M=Cu, then Y=PF₆ or ClO₄; r=s=v=1; t=u=0.

[0074] The rhodium or ruthenium catalysts are currently preferred,particularly if selected from those given below:

[0075] the compounds of form (VI):

[0076] in which M=Ru and X=Br; m=n=1; p=2; q=0;

[0077] or X=Cl; S═N(CH₂CH₃)₃; m=n=1; p=4; q=1;

[0078] or X=Cl; S=pyridine; m=n=1; p=q=2; and

[0079] the compounds of formula (VII):

[0080] in which M=Rh and Z=1,5-cyclooctadiene or norbornadiene; Y=BF₄,ClO₄, PF₆, OTf or BPh₄; r=s=t=v=1; u=0.

[0081] The catalysts comprising a ligand of formula (I) according to theinvention and a metal selected from rhodium, ruthenium, palladium,iridium, nickel and copper can be prepared by processes described in theliterature that are well known to those skilled in the art. Referencemay be made in particular to the patent application published under thenumber EP 850 945.

[0082] The catalysts according to the invention are generally preparedfrom a starting metal complex whose nature varies according to the metalselected.

[0083] In the case of the rhodium catalysts, the starting complex ise.g. one of the following compounds: Rh(cod)₂OTf; [Rh(cod)Cl]₂, wherecod denotes 1,5-cyclooctadiene; Rh(acac)(CO)₂, where acac denotesacetylacetonate; or Rh(acac)(C₂H₄)₂.

[0084] Complexes such as RuCl₃, Ru(cod)(methylallyl)₂, [RuCl₂(benzene)]₂and [RuCl₂(nbd)]., where nbd represents norbornadiene and x is aninteger, may be used to prepare the ruthenium catalysts. Ru(acac)₃ and[RuCl₂(cod)]_(x), where x is an integer, may also be mentioned.

[0085] In general terms, the metal catalysts according to the inventionare prepared by mixing the starting metal complex, a ligand of formula(I) and a degassed, anhydrous organic solvent and optionally maintainingthe reaction mixture at a temperature of between 15 and 150° C.,preferably of between 30 and 120° C., for e.g. 10 minutes to 5 hours.

[0086] Solvents which may be used are aromatic hydrocarbons (such asbenzene, toluene or xylene), amides (such as formamide,dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone orhexamethylphosphorylamide), alcohols (such as ethanol, methanol,n-propanol or isopropanol) and mixtures thereof, ketones (such asacetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone),ethers (such as e.g. tetrahydrofuran) and linear, branched or cyclicalkanes (such as pentane, hexane or methylcyclohexane).

[0087] The catalyst is then isolated by conventional techniques(filtration or crystallization) and used in asymmetric reactions.Nevertheless, the catalyst can also be prepared in situ. In this casethe reaction which is to be catalyzed by the catalyst prepared in thisway can be carried out without intermediate isolation of the catalyst.

[0088] The present invention further relates to the use of the metalcatalysts according to the present invention for the catalysis ofasymmetric reactions, especially hydrogenation reactions and reactionsfor the formation of C—C bonds. The asymmetric hydrogenation processesor processes for the asymmetric formation of C—C bonds which use suchcatalysts form an integral part of the invention. These processes arecarried out under conditions well known to those skilled in the art.

[0089] For example, in the case of an asymmetric hydrogenation reaction,the unsaturated substrate, dissolved in a solvent containing thecatalyst, is placed under hydrogen pressure. The operating conditionsare analogous to those commonly used with the metal catalysts of theprior art. For example, a hydrogen pressure of between 1 and 150 bar anda temperature of 0° C. to 150° C. will be used. The molar ratio ofsubstrate to catalyst generally varies from 1/100 to 1/100,000 andpreferably from 1/100 to 1/5000.

[0090] The rhodium complexes prepared from the ligands of the inventionare more particularly suitable for the asymmetric catalysis of olefinisomerization reactions, reactions for the hydrogenation of C═C bondsand 1,4-addition reactions of boronic acids.

[0091] The ruthenium complexes prepared from the ligands of theinvention are more particularly suitable for the asymmetric catalysis ofreactions for the hydrogenation of carbonyl bonds, C═C bonds and C═Nbonds.

[0092] In the Examples which follow, ‘Preparation’ denotes the Examplesdescribing the synthesis of intermediates and ‘Example’ denotes thosedescribing the synthesis of compounds of formula (I), (VI) or (VII)according to the invention. These Examples serve to illustrate theinvention and cannot under any circumstances limit its scope. Themelting points are measured on a Koffler bench and the nuclear magneticresonance spectral values are characterized by the chemical shift 8calculated relative to TMS, by the number of protons associated with thesignal and by the shape of the signal (s for singlet, d for doublet, tfor triplet, m for multiplet, dd for doublet of doublets, ddd fordoublet of doublet of doublets, q for quadruplet, qd for doublet ofquadruplets, J for coupling constant). The operating frequency and thesolvent used are indicated for each compound. The mass spectrometryresults are obtained with a Hewlett Packard 7989 A instrument.

[0093] The following abbreviations are used: RT=room temperature,DMSO=dimethyl sulfoxide, Ph=phenyl, THF=tetrahydrofuran, Me=methyl,Et=ethyl, acac=acetylacetonate, Tf=triflate;S-DPED=(S,S)-diphenylethylenediamine.

[0094] The nomenclature used to identify the compounds is thatrecommended by Chemical Abstracts.

[0095] Preparation 1

[0096] 6-Bromo-2,3-dihydro-1,4-benzodioxin, Compound V

[0097] 35 g of 1,4-benzodioxane and 200 ml of anhydrousdimethylformamide are placed under argon at 0° C. 54.9 g ofN-bromosuccinimide are then added in portions. After it has returnedgradually to room temperature, the reaction mixture is stirred for 24hours. The solvents are evaporated off under reduced pressure and thewhite solid obtained is washed with dichloromethane. The filtrate istreated with 50 ml of saturated aqueous sodium sulfate solution, washedwith 50 ml of saturated aqueous sodium chloride solution and dried overmagnesium sulfate. After evaporation of the solvents under reducedpressure, a yellow oil is obtained (quantitative yield).

[0098] EI mass spectrum: M⁺=214

[0099]¹H NMR (200 MHz) CDCl₃: 4.25 (4H, s); 6.74 (1H, d); 6.93 (1H, dd);7.02 (1H, d)

[0100] Preparation 2

[0101] 6-Bromo-2,3-dihydro-1,4-benzodioxin, Compound V

[0102] Compound V can also be prepared by the following procedure:

[0103] 5 g of 1,4-benzodioxane and 100 ml of anhydrous tetrahydrofuranare placed under argon in the dark. 5.12 g of1,3-dibromo-5,5-dimethylhydantoin are then added. The reaction mixtureis stirred at room temperature in the dark for 18 hours. After half ofthe tetrahydrofuran has been evaporated off, 50 ml of pentane are added.After filtration, the operation is repeated three times and the solventsare then evaporated off under reduced pressure. The oily residueobtained is purified by chromatography on a silica gel column using acyclohexane/ethyl acetate mixture (8/2, v/v) as the eluent (yield=90%).

[0104] Preparation 3

[0105] (2,3-Dihydro-1,4-benzodioxin-6-yl)diphenylphosphine, CompoundIVA.1

[0106] 11 g of compound V and 30 ml of anhydrous tetrahydrofuran areplaced under argon and cooled to −78° C. 25.6 ml of 2.2 M n-butyllithiumin dioxane are added dropwise and the reaction mixture is then stirredat −78° C. for 1 hour. 10.4 ml of chlorodiphenylphosphine are then addeddropwise, the temperature being maintained at −60° C. The temperature ofthe reaction mixture then rises slowly to 0° C. and 20 ml of saturatedammonium chloride solution are added at 0° C. The organic phase is thenwashed with 2 times 20 ml of saturated sodium chloride solution, driedover magnesium sulfate and filtered and the solvents are evaporated offunder reduced pressure to give an orange oil, which crystallizes. Thesolid is subsequently washed with hot hexane and then filtered off(yield=90%).

[0107]¹H NMR (200 MHz) CDCl₃: 4.26 (4H, m); 6.80-6.84 (2H, m); 6.85 (1H;d: J=4 Hz); 7.32 (10H, m)

[0108]³¹P NMR (162 MHz) CDCl₃: −4.66 ppm

[0109] Preparation 4

[0110] (2,3-Dihydro-1,4-benzodioxin-6-yl)diphenylphosphine oxide,Compound IIIA.1

[0111] 8 ml of 30% aqueous hydrogen peroxide solution are added dropwiseto a suspension of 16.3 g of compound IVA.1 in 60 ml of methanol, thetemperature of the reaction mixture being maintained below 40° C. Afterstirring for one hour, 14 ml of 30% aqueous sodium sulfite solution areadded. Stirring is maintained for 1 hour and 9 ml of 1 N aqueoushydrochloric acid solution are then added. The solution is concentratedat 40° C. and the aqueous residue is extracted with 50 ml ofdichloromethane. The organic phase is dried over magnesium sulfate andthe solvents are evaporated off under reduced pressure to give a yellowoil, which crystallizes. The solid obtained is washed with hot hexaneand then filtered off (quantitative yield).

[0112] EI mass spectrum: M⁺=335

[0113]¹H NMR (200 MHz) CDCl₃: 4.26 (4H, m); 6.95 (1H, dd: J=11.8 Hz,J=3.1 Hz); 7.09-7.18 (2H, m); 7.42-7.54 (6H, m); 7.61-7.72 (4H, m)

[0114]³¹P NMR (162 MHz) CDCl₃: 30.1 ppm

[0115] Preparation 4 bis

[0116] (2,3-Dihydro-1,4-benzodioxin-6-yl)diphenylphosphine oxide,Compound IIA.1

[0117] 100.0 g of 6-bromo-2,3-dihydro-1,4-benzodioxin diluted in 200 mlof anhydrous THF are added over about 1 hour, under nitrogen, to asuspension of 12.4 g of magnesium in 31 ml of anhydrous THF, thetemperature being maintained below 60° C. After the reaction mixture hasbeen maintained at 60° C. for 2 hours, 107.7 g ofchlorodiphenylphosphine are added over 3 hours without exceeding 10° C.in the reaction medium. After the temperature has been maintained at 20°C. for 18 hours, 35 ml of methanol are added. The reaction medium isstirred for one hour and then cooled to 0° C. 30 ml of 35% hydrogenperoxide are then added without exceeding 5° C. in the reaction mixture.After the temperature has been maintained at 20° C. for 2 hours and thesolvents have been evaporated off under reduced pressure, the solidobtained is dissolved in 900 ml of hot isopropyl acetate, then washedsuccessively with 3 times 200 ml of 1 N HCl, 150 ml of 1 N aqueouspotassium carbonate solution and 150 ml of water and then dried overmagnesium sulfate. After 500 ml of solvent have been evaporated offunder reduced pressure, the reaction mixture is cooled to 0° C. andfiltered and the solid is rinsed with 2 times 30 ml of isopropylacetate. After drying for 72 hours at 20° C. under reduced pressure, 113g of a creamy-white solid are obtained (yield=72%).

[0118] Preparation 5

[0119](S)-[5,5′-bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis(diphenylphosphineoxide), Compound IIA.1

[0120] 30 g of compound IIIA.1 and 600 ml of anhydrous tetrahydrofuranare degassed, placed under argon and then cooled to −100° C. with theaid of a cryostat. 65 ml of a 1.5 M solution of tert-butyllithium inpentane are added dropwise at −100° C. The reaction mixture is broughtto −70° C. over 30 minutes and then stirred at this temperature for 3hours 30 minutes. 19.8 g of anhydrous iron trichloride are then addedall at once under a stream of argon. The reaction mixture is then slowlybrought to room temperature and stirred for 12 hours. It is concentratedat 60° C. and 50 ml of 1 N aqueous sodium hydroxide solution and 500 mlof dichloromethane are added. The precipitate obtained is filtered offon Celite and then rinsed with 100 ml of dichloromethane. The organicphase is washed with 50 ml of water and 50 ml of saturated aqueoussodium chloride solution and dried over magnesium sulfate. After thesolvents have been evaporated off under reduced pressure, the solidobtained is dissolved in 150 ml of chloroform, and a solution of 12 g of(−)-L-dibenzoyltartaric acid in 180 ml of ethyl acetate is then added. Aprecipitate appears after a few minutes. This precipitate is filteredoff and then suspended in 200 ml of dichloromethane, and 100 ml of 1 Naqueous potassium hydroxide solution are added. The reaction mixture isstirred at room temperature for 30 minutes, after which the organicphase is separated off, washed with 50 ml of water and 50 ml ofsaturated aqueous sodium chloride solution and then dried over magnesiumsulfate. The solvents are then evaporated off under reduced pressure(yield=50%).

[0121]¹H NMR (200 MHz) CDCl₃: 3.42 (2H, m); 3.69 (2H, m); 3.92 (2H, m);4.06 (2H, m); 6.65 (2H, dd); 6.77 (dd); 7.26-7.56 (16H, m); 7.68 (4H, m)

[0122]³¹P NMR (162 MHz) CDCl₃: 30.97 ppm

[0123] CI mass spectrum: MH⁺=671

[0124] Melting point>260° C.

[0125] [α]_(D) ²⁰ (CHCl₃, C=1)=−140°

[0126] An X-ray structure of the complex of compound IIA.1 withL-dibenzoyltartaric acid revealed the (S) absolute configuration.

[0127] An analogous procedure is used to prepare compound IIA.2:(R)-[5,5′-bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis(diphenylphosphineoxide)

[0128] [α]_(D) ²⁰ (CHCl₃, C=1)=+143°

[0129] Preparation 6

[0130] (2,2-Difluoro-1,3-benzodioxol-5-yl)diphenylphosphine oxide,compound IIIA.2

[0131] 90.1 g of 5-bromo-2,2-difluoro-1,3-benzodioxole diluted in 168 mlof anhydrous THF are added over 2 hours, under nitrogen, to a suspensionof 10.2 g of magnesium in 25.2 ml of anhydrous THF, the temperaturebeing maintained at 60° C. After the reaction mixture has beenmaintained at room temperature for 3 hours, 90 g ofchlorodiphenylphosphine oxide are added over 2 hours without exceeding20° C. in the reaction mixture. After the reaction mixture has beenmaintained at 20° C. for 19 hours, it is hydrolyzed with 27 ml of waterand 135 ml of 1 N HCl and then extracted with 270 ml of ethyl acetate.After decantation and phase separation, the organic phase is washedsuccessively with 135 ml of 1 N HCl, 135 ml of saturated aqueouspotassium bicarbonate solution and 135 ml of water and then dried oversodium sulfate. The solvents are evaporated off under reduced pressureto give 128 g of a brown viscous oil. This oil is purified by filtrationon silica using an ethyl acetate/heptane mixture (varying from 50/50 to100/0, v/v) as the eluent (brown oil, 90 g, yield=66%).

[0132] CI mass spectrum: MH⁺=359

[0133]¹H NMR (300 MHz) CDCl₃: 7.70-7.41 (11H, m); 7.37 (1H, dd); 7.16(1H, dd)

[0134] Preparation 7

[0135] (2,2-Difluoro-4-iodo-1,3-benzodioxol-5-yl)diphenylphosphineoxide, compound IIIC.1

[0136] 96.6 ml of a 2.5 M solution of butyllithium in hexane are addedover 40 minutes at 0° C., under nitrogen, to a solution of 35.5 ml ofdiisopropylamine diluted in 150 ml of anhydrous THF. After stirring for15 minutes at 0° C., the solution is added slowly over 1 hour, undernitrogen, to a solution of 82.5 g of compound IIIA.2 diluted in 600 mlof anhydrous THF at −78° C., and stirring is then maintained at −78° C.for 50 minutes. A solution of 60.9 g of iodine diluted in 250 ml ofanhydrous THF is added over one hour to the previous solution at −78° C.The reaction mixture is then brought slowly to room temperature andsubsequently stirred for 20 hours. It is then cooled to 0° C. andfiltered and the solid is rinsed with 3×20 ml of THF. After drying for 5hours at 40° C. under reduced pressure, 97.6 g of a creamy-white solidare obtained (yield=87.5%).

[0137] EI mass spectrum: M⁺=484

[0138]¹H NMR (250 MHz) CDCl₃: 7.73-7.48 (10H, m); 7.04-6.96 (2H, m)

[0139] Preparation 8

[0140](R,S)-[4,4′-bi(2,2-difluoro-1,3-benzodioxole)-5,5′-diyl]bis(diphenylphosphineoxide), racemic compound IIA.3

[0141] 30 g of compound IIIC.1, 11.8 g of copper powder and 150 ml ofDMF are heated at 130° C. for 4 hours. The reaction mixture issubsequently brought to room temperature, filtered and thenconcentrated. The brown oil obtained is subsequently diluted in 300 mlof dichloromethane, then washed successively with 100 ml of saturatedaqueous ammonium chloride solution and 100 ml of water and dried overmagnesium sulfate. The yellow solid obtained is then recrystallized from250 ml of methanol at 0° C. and dried under reduced pressure to give15.2 g of a white solid (yield=68.7%).

[0142] CI mass spectrum: M⁺=715

[0143]¹H NMR (300 MHz) CDCl₃: 7.66-7.25 (20H, m); 7.03-7.00 (4H, m)

[0144] Compound IIA.3 is then resolved by chromatography on a chiralphase column marketed under the name Chirose® C3 to give the opticallypure (S) and (R) enantiomers.

[0145] Preparation 9

[0146] Diphenyl (2,3-dihydro-1,4-benzodioxin-6-yl)phosphonate (compoundIIIB.1)

[0147] 602 mg (25.6 mM) of activated magnesium and 1 ml of anhydroustetrahydrofuran (THF) are placed in a three-necked round-bottom flaskunder argon. Two drops of 1,3-dibromopropane are added and 5 g (23.3 mM)of compound V dissolved in 10 ml of THF are then added, the temperaturebeing maintained at 0° C. The reaction mixture is stirred for 2 hours atroom temperature and then for 1 hour at the reflux point of the solvent.The magnesium compound formed is then added slowly to a solution of 4.84ml (23.25 mM) of diphenylphosphinic chloride in 5 ml of THF, cooled to−5° C. beforehand. The solution is stirred overnight at room temperatureand then concentrated under reduced pressure. The residue is taken up in20 ml of ethyl acetate and stirred with 10 ml of normal hydrochloricacid solution for 30 minutes. The aqueous phase is extracted with ethylacetate and the combined organic phases are washed with water, driedover magnesium sulfate and concentrated under reduced pressure. The oilobtained is purified by chromatography on silica gel using acyclohexane/ethyl acetate mixture (7/3, v/v) as the eluent to give 5 gof the expected product in the form of a pinkish-white solid(yield=59%).

[0148]¹H NMR (200 MHz, CDCl₃): δ=4.25-4.32 (m, 4H); 6.95 (dd, J=5.1, 8.1Hz, 1H); 7.10-7.35 (m, 10H); 7.39-7.43 (m, 1H); 7.47 (ddd, 1H)

[0149]¹³C NMR (50 MHz, CDCl₃): δ=64.1; 64.5; 117.7 (d, J=18.5 Hz); 120.5(d, J=4.5 Hz); 121.6 (d, J=12.7 Hz); 124.9; 125.9 (d, J=10.6 Hz); 129.6;143.5 (d, J=22.2 Hz); 147.9; 150.5 (d, J=7.4 Hz)

[0150]³¹P NMR (162 MHz, CDCl₃): δ=13.11

[0151] Mass spectrum (EI): M⁺=368

[0152] Preparation 10

[0153] Diethyl (2,3-dihydro-1,4-benzodioxin-6-yl)phosphonate (CompoundIIIB.2)

[0154] 20 g (92.8 mM) of the compound obtained according to Preparation1 and 1.2 g (9.28 mM) of nickel chloride are placed in a round-bottomflask equipped with a distillation apparatus. The mixture is stirred andbrought to 160° C. and 18.8 ml (111.4 mM) of triethyl phosphite areadded dropwise. The reaction mixture is stirred at 160° C. for one hourafter the addition has ended, while the bromoethane formed by thereaction is collected by distillation. The reaction medium is thencooled and 50 ml of ethyl ether and 50 ml of ethyl acetate are added.The suspension obtained is filtered and the filtrate is concentratedunder reduced pressure. The residue is then purified by chromatographyon silica gel using ethyl acetate as the eluent to give 25 g of theexpected product in the form of a colorless oil (quantitative yield).

[0155]¹H NMR (400 MHz, CDCl₃): δ=1.24 (t, J=7.0 Hz, 6H); 4.01 (qd,J=7.0, 9.9 Hz, 4H); 4.20-4.23 (m, 4H); 6.86 (dd, J=8.1, 4.6 Hz, 1H);7.19-7.22 (m, 2H)

[0156]¹³C NMR (50 MHz, CDCl₃): δ=16.1; 61.8; 64.0; 64.4; 117.5 (d,J=17.5 Hz); 120.9 (d, J=12.0 Hz); 125.3 (d, J=10.0 Hz); 125.5; 143.4 (d,J=20.8 Hz); 147.2

[0157]³¹P NMR (162 MHz, CDCl₃): δ=20.20

[0158] Mass spectrum (EI): M⁺=272

[0159] Preparation 11

[0160] Tetraphenyl[5,5′-bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]-diphosphonate (CompoundIIB.1)

[0161] A solution of 0.675 ml (3.97 mM) of tetramethylpiperidine in 5 mlof THF is prepared and cooled to −78° C. and 1.32 ml (3.24 mM) of a 2.4M solution of n-butyllithium in hexane are added. The solution isstirred for 30 min at −15° C. and then added to a solution of 1 g (2.27mM) of compound IIIB.1 in 5 ml of THF, cooled to −78° C. The mixture isstirred for 1 hour at −78° C. and 570 mg (3.5 mM) of anhydrous ferricchloride are then added. The mixture is stirred overnight at roomtemperature and then concentrated under reduced pressure. The residue istaken up in 30 ml of dichloromethane and stirred for 30 min in thepresence of 15 ml of N sodium hydroxide solution. The mixture isfiltered and the organic phase is separated off and washed successivelywith 15 ml of water, 15 ml of N hydrochloric acid solution, 10 ml ofwater and 10 ml of saturated sodium chloride solution. This organicphase is then dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by chromatography on silicagel using a cyclohexane/ethyl acetate mixture (1/1, v/v) as the eluentto give 200 mg of the expected product in the form of a pale yellowsolid (yield=20%).

[0162]¹H NMR (200 MHz, CDCl₃): δ=3.80-3.90 (m, 2H); 3.95-4.10 (m, 4H);4.144.30 (m, 2H); 6.88 (dd, J=8.2, 17.7, 8H); 7.00-7.22 (m, 14H); 7.72(dd, J=14.5, 8.4 Hz, 2H)

[0163]¹³C NMR (50 MHz, CDCl₃): δ=63.8; 64.2; 116.8 (d, J=18.5 Hz);120.8; 124.5; 126.9 (d, J=9.8 Hz); 129.2; 142.3 (d, J=22.1 Hz); 147.6;150.5 (d, J=8.1 Hz)

[0164]³¹P NMR (162 MHz, CDCl₃): δ=11.68

[0165] Mass spectrum (CI): (M+H)⁺=735

[0166] Preparation 12

[0167] Tetraethyl[5,5′-bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]-diphosphonate (compoundIIB.2)

[0168] A solution of 6.72 ml (44.4 mM) of TMEDA(tetramethylethylenediamine) and 5 g (18.5 mM) of compound IIB.2 in 50ml of THF is prepared and 20.2 ml (22.2 mM) of a 1.1 M solution ofsec-butyllithium in hexane are added at −60° C. The solution is stirredfor 2 h at −60° C. and 3.91 g (24 mM) of anhydrous ferric chloride arethen added all at once at −60° C. The mixture is stirred overnight atroom temperature. It is concentrated under reduced pressure and taken upin 100 ml of dichloromethane and 30 ml of 1 N sodium hydroxide solutionand the suspension is stirred for 30 min. After filtration, the organicphase is washed with water and then successively with 30 ml of Nhydrochloric acid solution, 30 ml of water and 30 ml of saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The solid residue is crystallized(ethyl ether/hexane, 1:1) to give 1.6 g of the expected compound in theform of a white solid (yield=32%).

[0169]¹H NMR (400 MHz, CDCl₃): δ=1.13 (q, J=7.0 Hz, 12H); 3.69-3.80 (m,2H); 3.85-3.92 (m, 6H); 4.14-4.17 (m, 4H); 4.22-4.24 (m, 4H); 6.90 (dd,J=4.0, 8.3 Hz, 2H); 7.41 (dd, J=13.8, 8.5 Hz, 2H)

[0170]¹³C NMR (50 MHz, CDCl₃): δ=16.1; 61.2 (d, J=8.0 Hz); 63.9; 64.2;116.2 (d, J=17.3 Hz); 125.2; 125.9 (d, J=9.1 Hz); 128.8 (d, J=12.1 Hz);141.8 (d, J=20.8 Hz); 146.5

[0171]³¹P NMR (162 MHz, CDCl₃): δ=19.13

[0172] Mass spectrum (EI): M⁺=542

[0173] Preparation 13

[0174] [5,5′-Bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]diphosphonyltetrachloride (compound IIC)

[0175] 2 g (3.69 mM) of compound IIB.2, 16 ml of thionyl chloride and0.4 ml of dimethylformamide are introduced into a round-bottom flaskfitted with a condenser, under an argon atmosphere, and refluxed (80-90°C.) for 4.5 h. The solution turns bright yellow. The mixture isconcentrated under reduced pressure and dried to give a dark orangesolid (needles), which can be kept in the refrigerator under an argonatmosphere until used directly in the next step.

[0176]¹H NMR (400 MHz, CDCl₃): δ=4.17-4.36 (m, 8H); 7.06 (dd, J=8.7, 5.8Hz, 2H); 7.54 (dd, J=20.0, 8.7 Hz, 2H)

[0177]³¹P NMR (162 MHz, CDCl₃): δ=34.74

[0178] Preparation 14

[0179][5,5′-Bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis[di(4-methylphenyl)-phosphineoxide], compound IIA.4

[0180] 19.9 ml (36.9 mM) of a 1.85 M solution of n-butyllithium inhexane are added at −78° C. to a solution of 6.3 g (36.9 mM) of4-bromotoluene in 50 ml of THF. A white suspension appears. The solutionis stirred for 1 h at −78° C. and then added to a solution of 1.86 g(3.69 mM) of compound IIC in 10 ml of THF. The solution turns darkbrown. The mixture is subsequently brought to room temperature and thenstirred for 1 h at 50° C. 20 ml of saturated ammonium chloride solutionare added and the organic phase is washed with water and then withsaturated sodium chloride solution, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography on silica gel using an ethyl acetate/methanol mixture(9/1, v/v) as the eluent to give 1.32 g of the expected compound in theform of a beige solid (yield=50% over two steps).

[0181]¹H NMR (400 MHz, CDCl₃): δ=2.30 (s, 6H); 2.38 (s, 6H); 3.57 (ddd,J=2.3, 7.2, 11.4 Hz, 2H); 3.75 (ddd, J=2.4, 4.3, 11.6 Hz, 2H); 3.97(ddd, J=2.3, 4.2, 11.2 Hz, 2H); 4.09 (ddd, J=2.6, 7.2, 11.1 Hz, 2H);6.65 (dd, J=8.5, 13.2 Hz, 2H); 6.74 (dd, J=3.0, 8.4 Hz, 2H); 7.04 (dd,J=2.4, 8.0 Hz, 4H); 7.20 (dd, J=2.1, 8.0 Hz, 4H); 7.32 (dd, J=8.0, 11.8Hz, 4H); 7.53 (dd, J=8.0, 11.4 Hz, 4H)

[0182]¹³C NMR (50 MHz, CDCl₃): δ=21.4; 63.4; 64.0; 115.8; 126.5 (d,J=13.3 Hz); 128.4 (d, J=12.3 Hz); 132.1 (d, J=10.4 Hz); 132.4; 132.9;135.8; 140.9; 142.5; 145.7

[0183]³¹P NMR (162 MHz, CDCl₃): δ=30.95

[0184] Mass spectrum (CI): (M+H)⁺=727

[0185] Preparation 15

[0186][5,5′-Bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis[bis(3,5-dimethylphenyl)phosphineoxide], compound IIA.5

[0187] This compound is obtained by following an analogous procedure toPreparation 13, starting from 5-bromo-m-xylene.

[0188]¹H NMR (400 MHz, CDCl₃): δ=2.12 (s, 12H); 2.31 (s, 12H); 3.63-3.66(m, 2H); 3.75-3.79 (m, 2H); 4.00-4.04 (m, 2H); 4.08-4.13 (m, 2H);6.72-6.75 (m, 4H); 6.96 (s, 2H); 7.11 (d, J=12.7 Hz, 6H); 7.29 (d,J=12.0 Hz, 4H)

[0189]¹³C NMR (50 MHz, CDCl₃): δ=21.0; 21.3; 63.4; 63.9; 115.9 (d,J=15.4 Hz); 126.6 (d, J=12.9 Hz); 129.8; 132.5; 134.1; 136.1; 137.1;141.0 (d, J=14.9 Hz); 145.5

[0190]³¹P NMR (162 MHz, CDCl₃): δ=31.78

[0191] Mass spectrum (CI): (M+H)⁺=783

EXAMPLE 1

[0192](S)-[5,5′-bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis(diphenylphosphine),compound I.1

[0193] 2.12 ml of tributylamine and then 780 μl of trichlorosilane areadded to 500 mg of compound IIA.1 and 5 ml of degassed distilled xylene,placed under argon. The reaction mixture is heated at 140° C. for 12hours. When it has returned to room temperature, 5 ml of 4 N aqueoussodium hydroxide solution are added. The reaction mixture is thenstirred at room temperature for 30 minutes and 15 ml of dichloromethaneare added. The organic phase is washed with 5 ml of distilled water andthen with 5 ml of saturated aqueous sodium chloride solution andsubsequently concentrated under reduced pressure. 10 ml of methanol arethen added and the white precipitate obtained is filtered off underargon, washed with 10 ml of methanol and then dried under reducedpressure for 4 hours (yield=91%).

[0194] [α]_(D) ²⁰ (benzene, C=0.1)=−44°

[0195] The following compounds are prepared in the same manner:

[0196](R)-[5,5′-bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis(diphenylphosphine),compound I.2

[0197]¹H NMR (200 MHz) CDCl₃: 3.35 (2H, m); 3.83 (4H, m); 4.13 (2H, m);6.62 (2H, dd: J=8 Hz, J=3 Hz); 6.85 (2H, d: J=8 Hz); 7.09 (4H, m); 7.23(8H, m); 7.31 (8H, m)

[0198]³¹P NMR (162 MHz) CDCl₃: −14.3 ppm [α]_(D) ²⁰ (benzene,C=0.1)=+44°

[0199](R)-[4,4′-bi(2,2-difluoro-1,3-benzodioxole)-5,5′-diyl]bis(diphenylphosphine),compound I.3

[0200] [α]_(D) ²⁰ (CH₃OH, C=0.5)=+48°

[0201](S)-[4,4′-bi(2,2-difluoro-1,3-benzodioxole)-5,5′-diyl]bis(diphenylphosphine),compound I.4

[0202] [α]_(D) ²⁰ (CH₃OH, C=0.5)=−49°

[0203][5,5′-Bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis[di(4-methylphenyl)-phosphine],compound I.5

[0204]¹H NMR (200 MHz, CDCl₃): δ=2.29 (s, 6H); 2.33 (s, 6H); 3.32-3.44(m, 2H); 3.74-3.94 (m, 4H); 4.034.18 (m, 2H); 6.62 (m, 2H); 6.82 (d,J=8.4 Hz, 2H); 6.87-7.23 (m, 16H)

[0205][5,5′-Bi(2,3-dihydro-1,4-benzodioxin)-6,6′-diyl]bis[bis(3,5-dimethylphenyl)phosphine],compound I.6

[0206]¹H NMR (400 MHz, CDCl₃): δ=2.12 (s, 12H); 2.25 (s, 12H); 3.47(ddd, J=2.3, 4.3, 12.0, 2H); 3.83 (ddd, J=2.1, 6.9, 11.6, 2H); 3.95(ddd, J=2.2, 4.5, 11.4, 2H); 4.14 (ddd, J=2.3, 7.2, 11.2, 2H); 6.63-6.67(m, 6H); 6.80 (m, 4H); 6.90 (d, J=8.1 Hz, 6H)

[0207]³¹P NMR (162 MHz, CDCl₃): δ=−14.52

EXAMPLE 2

[0208] Compound VII.1: Complex [Ru₂Cl₅L₂]-[(C₂H₅)₂NH₂]⁺ where L=compoundI.1

[0209] 50 mg of bis(benzenedichlororuthenium), 128 mg of compound I.1and 21.6 mg of diethylamine hydrochloride in 10 ml of tetrahydrofuranare refluxed for 16 hours. The solvents are then evaporated off underreduced pressure. The solid obtained is dried under reduced pressure.

[0210]³¹P NMR (162 MHz) CDCl₃: 51.1 (d); 54.4 (d) J=38 Hz

EXAMPLE 3

[0211] Compound VI.1: Complex [LRuCl₂(pyridine)₂] where L=compound I.2

[0212] 42.2 mg of (norbornadiene)RuCl₂(pyridine)₂, 63.9 mg of compoundI.2 and 15 ml of degassed anhydrous CH₂Cl₂ are then added and thereaction mixture is stirred for 12 hours under argon at roomtemperature. The solution is concentrated and dried under reducedpressure to give 96 mg of an orange-yellow solid.

[0213]³¹P NMR (162 MHz) CDCl₃: 40.9 ppm

EXAMPLE 4

[0214] Compound VI.2: Complex [LRuCl₂S-DPED] where L=compound I.2

[0215] 34 mg of [LRuCl₂(pyridine)₂] obtained in EXAMPLE 3, 7.4 mg of(S,S)-diphenylethylenediamine and 5 ml of degassed anhydrous CH₂Cl₂ arestirred for 2 hours under argon at room temperature. The solution isconcentrated and dried under reduced pressure to give 96 mg of anorange-yellow solid.

[0216]³¹P NMR (162 MHz) CDCl₃: 48.1 ppm

EXAMPLE 5

[0217] Compound VII.2: Complex [LRhcod]⁺BF₄ ⁻ where L=compound I.2

[0218] 50 mg of [Rh(cod)₂]+BF₄ and 58.6 mg of compound I.2 are placed ina Schlenk tube. The system is placed under argon by means of 3successive vacuum/argon purges. 10 ml of THF are then added and thereaction mixture is stirred for 30 minutes. After evaporation of thesolvent, the residue obtained is dried under vacuum to give 110 mg of ayellow powder.

EXAMPLE 6

[0219] Asymmetric Hydrogenation

[0220] General Methods:

[0221] a) with chiral ruthenium catalysts, prepared in situ, of theformula [LRuBr₂] where L=compound (I)

[0222] 2.2 equivalents of a 0.16 N-0.19 N solution of hydrobromic acidin methanol are added dropwise to 3.2 mg of(1,5-cyclooctadiene)bismethylallylruthenium and 1.1 equivalents ofcompound (I) in 1 ml of acetone under argon. After stirring for 30minutes at room temperature, the solvents are evaporated off underreduced pressure.

[0223] The substrate to be hydrogenated (1 mmol) is then dissolved in 2ml of hydrogenation solvent (of the alcohol or halogenated type, such asdichloromethane) and placed in an autoclave in the presence of thecatalyst under the desired hydrogen pressure and at the desiredtemperature.

[0224] b) with ruthenium trichloride

[0225] The substrate to be hydrogenated (1 mmol), dissolved in 2 ml ofhydrogenation solvent, is added to 2.1 mg of ruthenium trichloride and1.1 equivalents of compound (I). The hydrogenation is performed in anautoclave for the necessary time at the desired pressure andtemperature.

[0226] c) with the complex described in EXAMPLE 2

[0227] The substrate to be hydrogenated (1 mmol), dissolved in 2 ml ofhydrogenation solvent, is added to 3.6 mg of complex. The hydrogenationis performed in an autoclave for the necessary time at the desiredpressure and temperature.

[0228] The catalysts according to the invention for stereoselectivehydrogenation are useful for carrying out reductions of the followingtype: [Ru] ee (%) (configuration) [LRuBr₂] in situ 98.5 (R) CompoundVII.1*: [Ru₂Cl₅L₂]⁻[(C₂H₅)₂NH₂]⁺ 98.2 (R)

[0229] The enantiomeric excesses (ee) obtained by the hydrogenation ofdifferent substrates are shown in TABLE 1 below by way of example, theconditions used not being optimized (the letters indicated in the [Ru]column refer to the method of preparation of the catalyst). TABLE 1 T P(° C.) Time Substrate [Ru] (bar) solvent (h) Ligand ee (%)

(a) 4 50 MeOH 24 I.2 >99 (R)

(b) 4 50 MeOH 24 I.1 >99 (S)

(a) 4 50 MeOH 24 I.2 >99 (R)

(a) 4 50 EtOH 24 I.2 >99 (R)

(a) 4 50 EtOH 24 I.2 >99 (S)

(b) 20 50 EtOH 64 I.2 >99 (S)

(a) 30 30 MeOH 24 I.2   98.5 (R)

(a) 20 RT MeOH 64 I.2 >99 (R, R)

(a) 20 50 MeOH 24 I.1   93 (S)

(c) 20 50 MeOH 24 I.1   91 (S)

(a) 40 50 CH₂Cl₂/ MeOH 24 I.2   91 (R)

(a) 20 50 MeOH 24 I.1   91.5 (S)

(a) 4 50 MeOH 24 I.3 >99 (R)

(a) 20 50 EtOH 24 I.1   94 (S)

(a) 15 80 EtOH 24 I.1   63 (S)

(a) 10 80 EtOH 24 I.1   97 (S)

(a) 20 99 EtOH 24 I.1   49 (R)

(a) 20 99 EtOH 24 I.1   63 (R)

(a) 5 50 MeOH 24 I.1 >99 (S)

(a) 10 50 EtOH 24 I.1 >99 (S)

(a) 20 99 EtOH 24 I.4 70 (R)

(a) 20 99 EtOH 24 I.4   75 (R)

(a) 10 110 EtOH 3 I.4   80 (R)

(a) 5 50 MeOH 24 I.4   96 (S)

(a) 10 80 EtOH 3 I.2   88 (S)

(a) 10 80 EtOH 3 I.3   89 (S)

(a) 10 80 EtOH 3 I.2 97 (S)

EXAMPLE 7

[0230] Asymmetric 1,4-addition

[0231] 1 ml of dioxane, 0.1 ml of distilled water and 0.4 mmol ofcyclohexenone are added to 3.1 mg of Rh(acac)(C₂H₄)₂, 0.012 mmol ofcompound I.1 and 2 mmol of phenylboronic acid under argon. The reactionmixture is heated at 100° C. for 5 hours. After it has returned to roomtemperature, the solvents are evaporated off under reduced pressure. Theresidue obtained is dissolved in 20 ml of ethyl acetate, washed with 5ml of saturated aqueous sodium hydrogencarbonate solution and then driedover sodium sulfate. The solvents are then evaporated off under reducedpressure. The product is purified by filtration on silica to isolate(S)-3-phenylcyclohexanone, which is characterized by the ¹H NMR spectrumbelow.

[0232]¹H NMR (200 MHz) CDCl₃: 1.84 (2H, m); 2.16 (2H, m); 2.46 (4H, m);3.0 (1H, m); 7.21-7.45 (5H, m)

[0233] Enantiomeric excess: 96% ee (determined by Lipodex A chiral GPC)

EXAMPLE 8

[0234] TABLE 2 below shows a comparison of the results of thehydrogenation of different substrates obtained on the one hand with theruthenium complexes according to the invention and on the other handwith complexes of the type Ru-Binap, under the same operating conditions(temperature, pressure and solvent).

[0235] TABLE 2 shows a comparison of the results obtained in TABLE 1with the complexes according to the invention and the results obtainedwith the corresponding complexes in which the ligand (1) according tothe invention has been replaced by the ligand BINAP. TABLE 2 Li- ee (%)Substrate [Ru] gand (I) BINAP

(a) (R) >99 (R) >99 (R)

(a) (R) >99 (R) >99 (R)

(a) (R) >99 (R) >99 (R)

(a) (R) >99 (S) >99 (S)

(b) (R) >99 (S)   98 (S)

(a) (R)   98.5 (R)   96 (R)

(a) (S)   90 (S)   82 (S)

(a) (R) >99 (R, R) d.e. >99 >99 (R, R) d.e. = 95

(a) (S)   93 (S)   90 (S)

(a) (R)   91 (R)   90 (R)

(a) (S)   94 (S)   84 (S)

(a) (S)   63 (S)   56 (S)

(a) (S)   97 (S)   88 (S)

(a) (S)   49 (R)   23 (R)

(a) (S)   63 (R)   44 (R)

(a) (S)   99 (S)   92 (S)

1. A compound, in optically pure or racemic form, of formula (I):

in which: R₁ and R₂ each independently are: a (C₅-C₇)cycloalkyl group, aphenyl group optionally substituted by one or more (C₁-C₄)alkyl,(C₁-C₄)alkoxy or di(C₁-C₄)alkylamino groups or by a halogen atom, or a5-membered heteroaryl group; and A is an ethylene group (CH₂—CH₂) or aCF₂ group.
 2. The compound of formula (I) according to claim 1, whereinR₁ and R₂ are identical.
 3. The compound of formula (I) according toclaim 2, wherein R₁ and R₂ are a phenyl group.
 4. Intermediates offormula (IIA) useful for the preparation of the compound of formula (I)according to claim 1:

in which R₁, R₂ and A are as defined for (I) in claim
 1. 5.Intermediates of formula (IIB) useful for the preparation of thecompound of formula (I) according to claim 1:

in which A is as defined for (I) in claim 1 and R is a (C₁-C₄)alkylgroup or an ally substituted phenyl group.
 6. Intermediates of formula(IIIA) useful for the preparation of the compound of formula (I)according to claim 1:

in which R₁, R₂ and A are as defined for (I) in claim
 1. 7.Intermediates of formula (IIIC) useful for the preparation of thecompound of formula (I) according to claim 1:

in which R₁, R₂ and A are as defined for (I) in claim
 1. 8.Intermediates of formula (IVA) useful for the preparation of thecompound of formula (I) according to claim 1:

in which R₁, R₂ and A are as defined for (I) in claim
 1. 9. (canceled)10. A chiral metal catalyst, which comprises a compound of formula (I)according to claim 1 as a ligand.
 11. The chiral metal catalystaccording to claim 10, wherein said compound of formula (I) is inoptically pure form.
 12. The chiral metal catalyst according to claim10, wherein the metal is selected from the group consisting of rhodium,ruthenium, iridium, palladium, copper and nickel.
 13. The chiral metalcatalyst according to claim 12 of formula (VI):M_(m)L_(n)X_(p)S_(q)  (VI) in which: M is a metal selected from thegroup consisting of rhodium, ruthenium, iridium, palladium, nickel andcopper; L is a compound of formula (I); and X, S, m, n, p and q aredefined as follows: if M=Rh, then X=Cl, Br or I; m=n=p=2; q=0; if M=Ru,then: X=—OC(O)CH₃; m=n=1; p=2; q=0; or X=Br; m=n=1; p=2; q=0; or X=Cl;S═N(CH₂CH₃)₃; m=n=2; p=4; q=1; or X=methylallyl; m=n=1; p=2; q=0; orX═Cl; S=pyridine; m=n=1; p=q=2; or X=Cl; S=chiral 1,2-diamine; m=n=1;p=q=2 orp=2, q=1; if M=Ir, then X=Cl, Br or I; m=n=p=2; q=0; if M=Pd,then: X=Cl; m=n=1; p=2; q=0; or X=π-allyl; m=n=p=2; q=0; if M=Ni, thenX=Cl, Br or I; m=n=1; p=2; q=0.
 14. The chiral metal catalyst accordingto claim 12 of formula (VII): [M_(r)L_(s)Z_(t)W_(u)]Y_(v)  (VII) inwhich: M is a metal selected from the group consisting of rhodium,ruthenium, iridium, palladium and copper; L is a compound of formula(I); and Z, W, r, s, t, u and v are defined as follows: if M=Rh, thenZ=1,5-cyclooctadiene or norbornadiene; Y=BF₄, ClO₄, PF₆, OTf or BPh₄;r==t=v=1; u=0; if M=Ru, then: Z=Cl, Br or I; W=benzene or p-cymene;Y=Cl, Br or I; r=s=t=u=v=1; or Y=BF₄, ClO₄, PF₆ or BPh₄; r=s=1; t=u=0;v=2; or Z=Cl; Y=NH₂(C₂H₅)₂; r=s=2; t=5; u=0; v=1; if M=Ir, thenZ=1,5-cyclooctadiene or norbornadiene; Y=BF₄, ClO₄, PF₆ or BPh₄;r=s=v=1; t=1; u=0; if M=Pd, then Y=BF₄, ClO₄, PF₆ or BPh₄; r=s=v=1;t=u=0; if M=Cu, then Y=PF₆ or ClO₄; r=s=v=1; t=u=0.
 15. The catalyst offormula (VI) according to claim 13, wherein M=Ru and X=Br; m=n=1; p=2;q=0; or X=Cl; S=N(CH₂CH₃)₃; m=n=1; p=4; q=1; or X=Cl; S=pyridine; m=n=1;p=q=2.
 16. The catalyst of formula (VII) according to claim 14, whereinM=Rh and Z=1,5-cyclooctadiene or norbornadiene; Y=BF₄, ClO₄, PF₆, OTf orBPh₄; r=s=t=v=1; u=0.
 17. A catalytic hydrogenation process, whichcomprises hydrogenating a substrate in the presence of a catalystaccording to claim
 10. 18. (canceled)
 19. A catalytic hydrogenationprocess, which comprises hydrogenating a substrate in the presence of acatalyst according to claim
 11. 20. A catalytic hydrogenation process,which comprises hydrogenating a substrate in the presence of a catalystaccording to claim
 12. 21. A catalytic hydrogenation process, whichcomprises hydrogenating a substrate in the presence of a catalystaccording to claim
 13. 22. A catalytic hydrogenation process, whichcomprises hydrogenating a substrate in the presence of a catalystaccording to claim
 14. 23. A catalytic hydrogenation process, whichcomprises hydrogenating a substrate in the presence of a catalystaccording to claim
 15. 24. A catalytic hydrogenation process, whichcomprises hydrogenating a substrate in the presence of a catalystaccording to claim
 16. 25. A process for catalyzing the asymmetricreaction of a starting compound into an end compound, which comprisescarrying out the reaction in the presence of a catalyst according toclaim 10.